Most tumor cells express antigens at their surface which differ either qualitatively or quantitatively from the antigens present at the surface of the corresponding normal cells. These antigens are specific when they are expressed only by tumor cells. When they are present on both normal and tumor cells, these antigens are said to be associated with the tumor; in this case, they are present either in larger amounts or in a different form in the tumor cells.
The large majority of tumor antigens which have been characterized to date in man are human antigens associated with a tumor (hereinafter referred to as associated antigens). Among these, the following may be highlighted:
oncofetal antigens, such as carcinoembryonic antigen, which are present in fetal tissues and absent or in the trace state in the corresponding adult tissues; their expression is induced again in an aberrant manner during the development of a tumor; PA1 differentiation antigens, which are normally expressed only during certain stages of maturation of a particular cell type; tumor cells which express such an antigen are considered to have their origin in a cell blocked in its differentiation; PA1 the products of oncogenes which are beginning to be identified. PA1 the use (i) of a polypeptide recognized by antibody H23, or, alternatively, the use (ii) of a virus into the genome of which a DNA fragment coding for a polypeptide recognized by antibody H23 is inserted, for treating or preventing a malignant tumor; PA1 a method of curative treatment or prevention of a malignant tumor, which comprises the act of administering a therapeutically effective amount (i) of a polypeptide recognized by antibody H23 or, alternatively, (ii) of a virus into the genome of which a DNA fragment coding for a polypeptide recognized by antibody H23 is inserted, to a subject needing such a treatment. ("Therapeutically effective amount" is understood to mean an amount sufficient for implementing an effective therapy.)
The specificity of an antigen associated with a tumor is hence quantitative rather than qualitative, since it may be present in a normal individual in a localized manner or intermittently (feto-embryonic period) or in the trace state, and becomes hyperexpressed (expression increased by a factor of 10 to 1000 times) only during a process of tumorigenesis. When this antigen is expressed normally, it is recognized by the immune system as part of the "Self", while its hyperexpression or its aberrant expression can trigger a humoral or cellular immune response.
Generally speaking, there are two major types of immune response: the humoral type response which is characterized by the production of antibodies by B lymphocytes, and the cell-mediated immune response which involves effector cells, i.e. essentially macrophages and cytotoxic T lymphocytes, as well as cells that regulate the immune response, i.e. helper and suppressor T lymphocytes.
A cell-mediated immune response necessitates the cooperation of helper T lymphocytes and effector cells. This cooperation takes place, in particular, as a result of interleukin-2 and various other lymphokines which are secreted by activated helper T lymphocytes. Interleukin-2 thereafter induces the action of cytotoxic T lymphocytes, and the lymphokines trigger the phagocytosis response of the macrophages. Concomitantly, there likewise exists a mechanism that suppresses the cell-mediated immune response which employs suppressor T lymphocytes.
It is now well known that patients suffering from a cancer may develop a humoral and cell-mediated immune response. This has been revealed, in particular, by demonstrating that the serum of some patients contained anti-tumor antigen antibodies, and that their serum was capable of inhibiting the growth of cancer cells in vitro. Nevertheless, inasmuch as spontaneous tumor regressions are extremely rare, it appears that the immune response observed in vitro remains ineffective in vivo. Similarly, it is also known that tumor grafts are not often rejected, even in immune animals, whereas allografts always are.
Although an immune response may develop against a tumor, it is doubtful whether it is of real benefit to the patient. Everything seems to indicate that a tumor eludes the body's mechanisms of immune surveillance. Various models have been proposed, to explain this phenomenon; for a complete and detailed review, see Scientific American, Medecine, Chapter 6, VIII Tumor Immunology, 1990. In principle, tumor antigens are considered to play a not insignificant part in modifying or diverting the immune response in favor of the tumor rather than in favor of the individual.
In the light of the complexity of the immune response against tumors and the mediocre state of current knowledge in this field, the use of an anticancer vaccine is not at all obvious. Animal studies have shown that immunization using living or killed cancer cells could lead to rejection of a subsequent tumor graft. Attempts at immunization using acellular products have generally been less successful.
To date, the possibility of manufacturing a vaccine against a cancer employing an antigen associated with this cancer hence remains controversial. A major theoretical objection to this method of treatment lies in the fact that an immune response is not considered to be sufficient to prevent or treat a tumor and that it is highly doubtful that a vaccine could be protective, that is to say capable of preventing or retarding the development of a tumor.